Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([N:14]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)S(C2C=CC=CC=2[N+]([O-])=O)(=O)=O)[CH2:11][CH2:10][C@H:9]1[C:35]1[N:39]=[CH:38][O:37][N:36]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].SCC(O)=O.O[Li].O.CCOC(C)=O>CN(C=O)C>[CH2:28]([O:27][NH:14][C@H:12]1[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:35]2[N:39]=[CH:38][O:37][N:36]=2)[CH2:10][CH2:11]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1c1ncon1
Agent: O=C(O)CS
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1ncon1
Temperature: 30 °C
Reaction time: 17 h
Yield: 69.7 %

Procedure:
A mixture of (2S,5R)-tert-butyl5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (1.5 g, 2.683 mmol), HSCH2COOH (1.48 g, 16.1 mmol), LiOH.H2O (1.13 g, 26.83 mmol) in DMF (50 mL) was stirred at 30° C. for 17 hrs. EtOAc (150 mL) was then added and the mixture was washed with water (2×), and saturated sodium chloride (2×), dried over Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (gradient elution 0˜50% petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(benzyloxyamino)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (700 mg, 63%) as a pale yellow solid. ESI-MS (EI+, m/z): 375.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[C:26]([OH:28])[CH:25]=[C:24](Br)[CH:23]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:7]([C:6]1[CH:9]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=1[C:24]1[CH:25]=[C:26]([OH:28])[CH:27]=[C:22]([C:21]([O:20][CH3:19])=[O:30])[CH:23]=1)#[N:8]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Reactant: COC(=O)c1cc(O)cc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(O)cc(-c2ccc(C)cc2C#N)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
Under an atmosphere of nitrogen, a flask was charged with 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (2.1 g, 8.2 mmol), 3-bromo-5-hydroxy-benzoic acid methyl ester (1.5 g, 6.2 mmol), potassium phosphate (2.8 g, 13 mmol), tetrakis(triphenylphosphine)palladium(0) (400 mg, 0.35 mmol), 1,4-dioxane (90 mL), and water (20 mL). The reaction mixture was stirred at 85° C. overnight. After cooling, the mixture was filtered through Celite and the filter cake was washed with EtOAc. The filtrate was concentrated and the residue was purified by silica gel column to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]O>>[Br:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1Br
Product: COC(=O)c1ccc([N+](=O)[O-])cc1Br

Procedure:
Compound 26 in methanol was treated with SO2Cl2 and the resulting solution heated at reflux for18 h. The reaction mixture was then evaporated, pre-absorbed on silica (Merck, 9385) and purified by chromatography, eluting with 10% ethyl acetate/i-hexane. Appropriate fractions were combined and evaporated to give methyl 2-bromo-4-nitro-benzoate (compound 27).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]#[N:17]>>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: c1ccc(CC2CCNCC2)cc1
Product: N#CCN1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Benzyl-piperidine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=215.2: AtRet=2.90.
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:31][CH:30]([CH3:32])[CH2:29][C@@H:25]([NH:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:10][CH2:9][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)(=[O:23])=[O:22])[C:26]([OH:28])=[O:27]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@@H](NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)C(=O)O

Procedure:
In a manner similar to Example 3(b), 4-phenyl-piperidine hydrochloride was condensed with (R)-2-(4-fluoro-benzenesulfonylamino]-4-methyl-pentanoic acid to give the title compound, mp=163-165° C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25]2)[O:7]1)(=[O:3])[CH3:2].ClCCl.Br[C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1.[Cl-].[Cl-].[Cl-].[Al+3].[OH2:51]>C(Cl)(Cl)Cl>[C:1]([O:4][CH2:5][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([O:20][C:21](=[O:23])[CH3:22])[C@H:8]([N:24]2[C:32]3[C:27](=[C:28]([CH3:33])[CH:29]=[CH:30][CH:31]=3)[C:26]([C:42](=[O:43])[C:41]3[CH:45]=[CH:46][C:38]([OH:51])=[CH:39][CH:40]=3)=[CH:25]2)[O:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(=O)c3ccc(O)cc3)c3c(C)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 46.09 %

Procedure:
To a 0.5 L stirred round bottom, purged with nitrogen, charge in order: [(2R,3R,4S,5R,6R)-3,4,5-triacetoxy-6-(4-methylindol-1-yl)tetrahydropyran-2-yl]methyl acetate (29.5 mmol), dichloromethane (100 mL), and 4-bromobenzoyl chloride (30.9 mmol). Cool the mixture in an icebath and add aluminum trichloride (88.4 mmol). After stirring, with cooling, for 1.5 hours, pour the reaction mixture over ice and dilute with water (100 mL) and chloroform (100 mL). Separate the organic phase and wash the aqueous with chloroform (100 mL). Combine the organics and wash with concentrated sodium bicarbonate solution (200 mL) and brine (200 mL). Dry over sodium sulphate, filter, and concentrate. Purify by flash chromatography over silica gel (330 g) eluting with 5-25% EtOAc/chloroform to give the title compound (7.9 g; 46.09% yield): mass spectrum (m/z): 582.4 (M+1), 580.4 (M−H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:26]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].O>[Fe].C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)cc1
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Oc2ccc(N)c(OCc3ccccc3)c2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
A mixture of 2-(benzyloxy)-4-[4-(methylsulfonyl)phenoxy]-1-nitrobenzene (11.0 g), iron powder (7.6 g), calcium chloride (0.3 g), water (30 mL), and ethanol (120 mL) was stirred at 80° C. for 2 hr. The reaction solution was filtered through celite, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from toluene and the obtained crystals were washed with diethyl ether to give the title compound (9.3 g, yield 92%) as pale-brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-:15].[Al+3].[Cl-].[Cl-].Cl.Cl[CH:21]([Cl:25])[CH:22](Cl)Cl>>[Cl:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([C:3]1[C:4]([OH:5])=[CH:22][C:21]([Cl:25])=[CH:10][C:2]=1[Cl:15])=[O:5]
Reactant: CS(=O)(=O)c1ccc(C(=O)Cl)c(Cl)c1
Reactant: [Cl-]
Reactant: ClC(Cl)C(Cl)Cl
Agent: Cl
Agent: [Al+3]
Product: CS(=O)(=O)c1ccc(C(=O)c2c(O)cc(Cl)cc2Cl)c(Cl)c1
Temperature: 0 °C

Procedure:
3.00 g of 2-chloro-4-methylsulfonylbenzoyl chloride are added in portions at room temperature to a mixture of 1.97 g of 3,5-dichlorophenone and 3.23 g of aluminum chloride in 50 ml of 1,1,2,2-tetrachloroethane, and the mixture is subsequently refluxed for 7 hours. When cold, the reaction mixture is poured onto 100 g of ice and 20 ml of concentrated hydrochloric acid. The organic phase is removed, and the aqueous phase is extracted twice using 50 ml of dichloromethane. The combined organic phases are washed until neutral and subsequently extracted three times using in each case 25 ml of 2N sodium hydroxide solution. The combined alkaline extracts are brought to a pH of 2 using concentrated hydrochloric acid. The precipitate is filtered off, washed with water until neutral and dried. This gives 3.194 g (70% of theory) of 2,2', 4'-trichloro-6'-hydroxy-4-methylsulfonylbenzophenone in the form of colorless crystals with a melting point of 123°-126° C.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl>O1CCCC1.O>[F:22][C:23]1[CH:24]=[C:25]([CH2:26][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: Fc1cccc(CCl)c1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(F)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (125 mL), and N-(1,1- dimethylethyl)-3-methyl-2-pyridine carboxamide (1 equivalent), are charged and cooled to -40° C. under nitrogen. Two equivalents of n-butyllithium are then added over 40 minutes. When half the n-butyllithium is added the mixture turns purple. Sodium bromide (1.3 g) is added and 3-fluoro-benzyl chloride (1.05 equivalents) is added dropwise (1:1 solution in tetrahydrofuran) over 40-50 minutes while the temperature is maintained at -40° C. After 30 minutes at -40° C., the mixture is diluted with water (250 mL) and the organic phase separated. This phase is dried over sodium sulphate and the solvent removed yielding an oil from which solid product, 3-[2-chromatograph. (3-fluoro-phenyl)ethyl]-N-(l,l-dimethylethyl)-2-pyridine carboxamide, may crystallize.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>C(Cl)Cl>[C:8]([NH:17][C:18]1[CH:30]=[C:29]([CH2:31][CH2:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:28]=[CH:27][C:19]=1[C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(CCCc2ccccc2)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(CCCc2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
0.28 mL of triethylamine and 0.12 mL of benzoyl chloride were added to 3 mL of methylene chloride solution containing 0.31 g of tert-butyl 2-amino-4-(3-phenylpropyl)benzoate sequentially while ice-cooled and stirred at room temperature for 17 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography [eluent; hexane:ethyl acetate=20:1] to obtain 0.48 g of tert-butyl 2-(benzamido)-4-(3-phenylpropyl)benzoate as while solid.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[C:12]1([C:18]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClCCl.CO>[C:27]1([C:18]2([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[S:21](=[O:6])[CH2:20][CH2:19]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Solvent: CO
Solvent: ClCCl
Product: O=S1CCC(c2ccccc2)(c2ccccc2)C2CNCC21
Temperature: -3 °C
Reaction time: 1 h
Yield: 51.6 %

Procedure:
A solution of 15.4 g of 3-chloroperoxybenzoic acid (at 85%) in 400 cm3 of dichloromethane is added over 40 minutes to a solution, cooled to -3° C., of 25 g of (4aRS, 7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole in 500 cm3 of dichloromethane and 100 cm3 of methanol. After stirring for one hour at -3° C., the reaction mixture is washed with 200 cm3 of a 10% aqueous solution of potassium hydrogen carbonate and again with 100 cm3 of this same solution, then dried over magnesium sulphate and concentrated to dryness at 40° C. under reduced pressure (2.7 kPa). The residue is crystallized from 50 cm3 of ethyl acetate, the crystals are taken up in 200 cm3 of dichloromethane, the solution obtained is washed with 75 cm3 of a 1N aqueous solution of sodium hydroxide and then dried over magnesium sulphate and concentrated to dryness. The residue is crystallized from 30 cm3 of ethyl acetate, the crystals are washed with ethyl acetate, drained and dried. 13.6 g of (1RS,4aRS,7aRS)-4,4-diphenylperhydrothiopyrano[2,3-c]-pyrrole 1-oxide are obtained in the form of white crystals; melting point 174° C.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[F:26])[C:4]=2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=1.OB(O)[C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32]([OH:34])=[O:33].C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:14]1[C:4]2[N:5]=[C:6]([NH:8][CH:9]([CH2:12][OH:13])[CH2:10][OH:11])[N:7]=[C:2]([C:29]3[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=3)[C:32]([OH:34])=[O:33])[C:3]=2[CH:17]=[CH:16][C:15]1=[O:18]
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: O=c1ccc2c(Cl)nc(NC(CO)CO)nc2n1-c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(-c2nc(NC(CO)CO)nc3c2ccc(=O)n3-c2ccc(F)cc2F)c1
Yield: 90.8 %

Procedure:
A mixture of 4-chloro-8-(2,4-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (20 mg, 0.047 mmol), 3-(dihydroxyboranyl)benzoic acid (11.8 mg, 0.07 mmol), K2CO3 (20 mg, 0.14 mmol), tetrakis(triphenylphosphine)palladium (2 mg, 0.0017 mmol), dioxane (1.2 ml), and water (0.4 ml) was heated in a sealed microwave vessel at 150 degrees for 10 min. The cooled solution was treated with DCM (3 ml), passed through a hydrophobic frit directly onto a silica cartridge (2 g). The cartridge was eluted with EtOAc followed by EtOAc/MeOH (9:1) to provide the title compound as a brown solid (20 mg, 80%) LC-MS m/z 469 (M+H)+ retention 2.73 min.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:44]([CH3:45])[N:43]=[N:42][N:41]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH3:45])[N:43]=[N:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nnnn4C)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nnnn4C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 56.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methyl-tetrazol-5-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.60 g) in methylene chloride (18 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.19 g) in methylene chloride (12 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-methyl-tetrazol-5-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 232) (350 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[C:12]1[C:13](=[O:19])[CH2:14][CH2:15][C:16]=1[O:17]C.Cl.O.C(OCC)(=O)C>CC(C)=O>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][CH3:10])[CH:5]=[C:4]([CH3:11])[C:3]=1[CH:12]1[C:13](=[O:19])[CH2:14][CH2:15][C:16]1=[O:17]
Reactant: CC#Cc1cc(C)c(C2=C(OC)CCC2=O)c(C)c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC#Cc1cc(C)c(C2C(=O)CCC2=O)c(C)c1
Temperature: 60 °C

Procedure:
To a solution of 2-(2,6-dimethyl-4-prop-1-ynylphenyl)-3-methoxycyclopent-2-enone (0.193 g, 0.76 mmol) in acetone (2.0 ml) is added 2M hydrochloric acid (2.0 ml). The mixture is heated at 60°C. under microwave irradiation for 20 minutes, then distilled water and ethyl acetate are added and the phases separated. The aqueous phase is extracted with ethyl acetate (×3), and combined organic fractions are washed with brine, dried over magnesium sulfate, filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography (ethyl acetate and isohexane as eluant) to afford 2-(2,6-dimethyl-4-prop-1-ynylphenyl)cyclopentane-1,3-dione.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:28][O:27][C:25](=[O:26])[CH2:24][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:11][CH:12]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc(O)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(-c2ccc(CNC(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.7 %

Procedure:
A mixture of 4-{[(tert-butoxycarbonyl)amino]methyl}-4′-hydroxy-1,1′-biphenyl (2.05 g, 6.85 mmol), prepared in the previous step, methyl bromoacetate (648 μL, 6.85 mmol) and potassium carbonate (4.73 g, 34.2 mmol) in 50 mL of DMF was stirred under nitrogen at room temperature for 20 h (overnight). The reaction was partitioned between ethyl acetate and water. The organic layer was separated, extracted multiple times with water, dried (MgSO4) and the solvent removed under reduced pressure to give methyl[(4′-{[(tert-butoxycarbonyl)amino]methyl}[1,1′-biphenyl]-4-yl)oxy]acetate (2.46 g, 97%) as an off-white solid, mp 111-113° C. Elemental Analysis for C21H25NO5. Calc'd: C, 67.91; H, 6.78; N, 3.77 Found: C, 67.70; H, 6.74; N, 3.72
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:23]1([N:26]2[CH2:31][C:30]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[O:29][CH2:28][C:27]2=[O:37])[CH2:25][CH2:24]1>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[N:34]1[CH2:35][CH2:36][C:30]2([O:29][CH2:28][C:27](=[O:37])[N:26]([CH:23]3[CH2:24][CH2:25]3)[CH2:31]2)[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(Br)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCC(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of 2-bromo-2-(4-bromo-2-fluorophenyl)ethyl acetate (0.971 mmol) in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (2.91 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (1.019 mmol). The reaction was allowed to stir at room temperature overnight. The reaction solution was then diluted with water (50 mL) and was extracted four times with ethyl acetate. The combined organic layer was washed four times with water, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as an oil (385 mg, 76% yield). MS(ES)+ m/e 469.1/471.2 [M+H]+ (bromide isotope pattern).
Reaction SMILES: CC1C=[C:5]([N:7]2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3C=N[CH:49]=[CH:50][CH:51]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:5][N:7]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Reactant: CCOC(=O)c1sc(N2CCN(Cc3cccnc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccccn3)C2=O)sc1C(=O)O

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 319.1 (M+1).